title: A deficit of brain dystrophin impairs specific amygdala GABAergic transmission and enhances defensive behaviour in mice.
abstract: Duchenne muscular dystrophy (DMD) is accompanied by cognitive deficits and psychiatric symptoms. In the brain, dystrophin, the protein responsible for DMD, is localized to a subset of GABAergic synapses, but its role in brain function has not fully been addressed. Here, we report that defensive behaviour, a response to danger or a threat, is enhanced in dystrophin-deficient mdx mice. Mdx mice consistently showed potent defensive freezing responses to a brief restraint that never induced such responses in wild-type mice. Unconditioned and conditioned defensive responses to electrical footshock were also enhanced in mdx mice. No outstanding abnormality was evident in the performances of mdx mice in the elevated plus maze test, suggesting that the anxiety state is not altered in mdx mice. We found that, in mdx mice, dystrophin is expressed in the amygdala, and that, in the basolateral nucleus (BLA), the numbers of GABA(A) receptor alpha2 subunit clusters are reduced. In BLA pyramidal neurons, the frequency of norepinephrine-induced GABAergic inhibitory synaptic currents was reduced markedly in mdx mice. Morpholino oligonucleotide-induced expression of truncated dystrophin in the brains of mdx mice, but not in the muscle, ameliorated the abnormal freezing response to restraint. These results suggest that a deficit of brain dystrophin induces an alteration of amygdala local inhibitory neuronal circuits and enhancement of fear-motivated defensive behaviours in mice.
authors.affiliation: Department of Degenerative Neurological Diseases, National Centre of Neurology and Psychiatry, Kodaira, Tokyo, Japan. elec1@ncnp.go.jp
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sekiguchi
authors.forename: Ko
authors.initials: K
authors.lastname: Zushida
authors.forename: Mikiharu
authors.initials: M
authors.lastname: Yoshida
authors.forename: Motoko
authors.initials: M
authors.lastname: Maekawa
authors.forename: Sari
authors.initials: S
authors.lastname: Kamichi
authors.forename: Mizuko
authors.initials: M
authors.lastname: Yoshida
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sahara
authors.forename: Shigeki
authors.initials: S
authors.lastname: Yuasa
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Takeda
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism*; D016189:Dystrophin / Q000172:deficiency* / Q000378:metabolism / Q000502:physiology; D005239:Fear / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D017966:Pyramidal Cells / Q000503:physiopathology; D011963:Receptors, GABA-A / Q000378:metabolism; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
chemical_list: D016189:Dystrophin; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid